Galectins are S-type lectins that bind β-galactose-containing glycoconjugates. Since the discovery of the first galectin in animal cells in 1975, fifteen mammalian galectins have been isolated and have been shown to be involved in diverse biological processes, such as cell adhesion, regulation of growth, and programmed cell death. Galectins have also been implicated in tumor development and progression, with Galectin-3 (“Gal-3”) having been shown to be involved in cancer cell adhesion, metastasis, angiogenesis, invasion, growth, and resistance to chemotherapies. See Ebrahim et al., “Galectins in cancer: carcinogenesis, diagnosis and therapy,” Ann. Transl. Med. 2(9):88 (2014).
Like other galectins, Gal-3 has a characteristic C-terminal carbohydrate recognition domain (“CRD”). Unlike other galectins, however, Galectin-3 also includes an amino-terminal domain that confers multivalent behavior. The amino-terminal domain allows Gal-3 to cross-link carbohydrate-containing ligands on cell surfaces and in the extracellular matrix, thereby modulating cell adhesion and signaling.
Alone, the C-terminal CRD of Gal-3 cannot cross-link carbohydrate-containing ligands on cell surfaces; without the N-terminal domain, the C-terminal CRD has no hemagglutination activity lacks the cooperative binding that characterize the intact lectin. Recombinantly expressed N-terminal truncations of Gal-3 protein that retain the C-terminal CRD but lack the amino-terminal multimerization domain have been demonstrated to act as dominant-negative inhibitors of Gal-3-mediated cross-linking, interfering with various tumor-associated properties in in vitro assays and inhibiting tumor growth and metastasis in animal models of various human cancers. Such N-terminal truncation proteins have thus been proposed for use in treating various human cancers.
For example, one such truncation, “Gal3C”, has been proposed for treatment of breast cancer, prostate cancer, colon cancer, lung cancer, and all solid and hematological forms of cancer, alone or in combination with chemotherapy, see U.S. Pat. No. 6,770,622; for treatment of multiple myeloma in combination with proteasome inhibitors such as bortezomib and carfilzomib, see U.S. Pat. No. 9,272,014; and for treatment of ovarian cancer, alone or in combination with chemotherapeutic agents such as paclitaxel, carboplatin, or bortezomib, see U.S. pre-grant publication 2015/0157691. U.S. pre-grant publication 2015/0216931 describes a small genus of N-terminal Gal-3 truncation proteins, collectively termed “Gal3M”, that contain one or more identified amino acid changes as compared to native human Gal-3. Recombinantly-expressed Gal3M proteins are predicted to be useful in treating solid tumors, including both carcinomas and sarcomas, and a wide range of hematological cancers, including B cell lymphoma, T cell lymphoma, NK cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myelocytic leukemia (“AML”), acute lymphocytic leukemia (“ALL”), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (“CML”), and myelodysplastic syndrome, either alone or in combination with proteasome inhibitors such as bortezomib and carfilzomib and other chemotherapeutic agents.
Despite the therapeutic promise of dominant-negative N-terminal Gal-3 truncation proteins, further optimization of Gal-3 dominant negative truncation proteins is still required. And despite the promise of dominant-negative N-terminal Gal-3 truncation proteins as treatments for those cancers for which the animal model data are widely accepted as predictive of efficacy in specific cancers, see e.g., Mirandola et al., “Anti-Galectin-3 Therapy: A New Chance for Multiple Myeloma and Ovarian Cancer?”, Int. Rev. Immunol., 33:417-427 (2014); and Pena et al., “Galectins as therapeutic targets for hematological malignancies: a hopeful sweetness”, Ann. Transl. Med. 2(9):87 (2014), the proposed extrapolation to additional cancers is predicated on a small number of galectin-3-mediated biological pathways that are thought to be shared by these additional cancers. There is, therefore, a need in the art to identify all cancers against which N-terminally truncated Gal-3 proteins will ultimately prove effective.